Expression of murine NKG2D ligands on tumor cells has been shown to be effective in inducing natural killer cells (NK cells) to eliminate tumor cells (i.e. tumor rejection). In humans, the MHC class I chain-related molecule A (MICA) and MICB (generally termed as MIC) are the most investigated NKG2D ligands, which were proposed to play roles in tumor rejection. Expression of MIC on the tumor cell surface can markedly enhance the sensitivity of tumor cells to NK cells in vitro and has been shown to inhibit the growth of human gliomas or small lung carcinomas in experimental models. These studies suggest that NK cells can potentially eliminate MIC-positive tumor cells in cancer patients. However, as clinically observed, most of the human epithelial tumors are found to be MIC+ rather than MIC−. It has been shown that tumor -derived soluble MIC (sMIC), which occurs as a result of MIC shedding by MIC+ tumor cells is one of the factors causing the ineffectiveness of NKG2D-mediated immunity in cancer patients. sMIC is believed to induce down-modulation of NKG2D expression on systemic and tumor infiltrated NK and T cells and thus result in functional impairment of NK and T cells in MIC+ cancer patients. A reduction in the density of MIC expressed on the tumor cell surface due to MIC shedding from tumors is also one of the mechanisms for tumor evasion.